1. Field of the Invention
This invention relates to a process for preparing 60-L-aspartyl-L-phenylalanine methyl ester, which is used as a sweetening agent.
2. Description of the Prior Art
Belgian Pat. No. 717,373 describes the sweetening characteristics, in particular for dietetic purposes, of the lower alkyl esters of 60-L-aspartyl-L-phenylalanine: ##STR1## Of these compounds, 60-L-aspartyl-L-phenylalanine methyl ester (where R is --CH.sub.3 in the preceding formula (I)), also known as 60-aspartame, is assuming particular commercial importance. In a known process of the art, the compounds (I) are obtained by a method which comprises reacting a lower alkyl eter of phenylalanine with an aspartic acid derivative in which the amino function is protected by a benzyloxycarbonyl group, and the .beta.-carboxy function by a benzyl ester group, the 60-carboxy group having previously been transformed into an ester function by rection with p-nitrophenol. The protector groups are then eliminated from the reaction product obtained in this manner. This process is complicated because of the many operations which are required, the use of numerous raw materials, and the mediocre overall yields, which makes the process uneconomical and little suitable for application on a commercial scale.
In French Pat. No. 7015787, the compounds of formula (I) are obtained by a process which comprises reacting L-aspartic anhydride, protected at the nitrogen by a formyl, carbobenzoxy or para-methoxycarbobenzoxy protector group, with a lower alkyl ester of L-phenylalanine, operating in an organic solvent. The nitrogen protector group is then eliminated from the reaction product obtained in this manner.
In published Japanese patent application Ser. No. 113,841/76 of 7.10.1976, a lower alkyl ester of N-formyl-60-L-aspartyl-L-phenylalanine is prepared by reacting a lower alkyl ester of L-phenylalanine with N-formyl-L-aspartic anhydride, operating in the presence of an organic acid having a dissociation constant of less than 10.sup.-4 at 25.degree. C. The reaction product obtained in this manner can then be treated for deformylation. In addition to giving the .alpha. isomer (preceding formula (I)), these known processes also give rise to the formation of rather large quantities of the .beta. isomer: ##STR2## the presence of which is undesirable. In this respect, it has been found that only the .alpha. isomer, and in particular the methyl derivative of said isomer (where R is --CH.sub.3 in the preceding formula (I)), has a sweetening power analogous to that of natural sugar and free from secondary tastes, whereas the methyl derivative of the .beta. isomer (where R is --CH.sub.3 in the preceding formula (II)) has a slightly bitter taste. A technical problem which arises in the processes under discussion is therefore to direct the reaction towards the prevalent formation of the .alpha. isomer.
However, when operating by the process of the aforesaid French patent, there is on the one hand poor reaction selectivity towards the formation of the .alpha. isomer, and on the other hand difficulty in controlling the ratio of the .alpha. to the .beta. isomer in the reaction products. In this respect, said ratio is strongly influenced by various factors such as the chosen solvent and the nature of the protective groups in that reaction stage in which the L-phenylalanine alkyl ester is reacted with L-aspartic anhydride protected at the nitrogen. The result is that said process is hardly attractive and of little interest for commercial application. When operating by the process of the aforesaid Japanese patent application, it is possible to control the reaction to a certain extent towards the prevalent formation of the .alpha. isomer. It has, however, been found that these more advantageous results in terms of selectivity towards the .alpha. isomer are obtained if large quantities of organic acid are present. This makes the process costly, and its operation is complicated particularly in the separation and recovery of the useful reaction products.